1-Aminocyclohexanes, such as Memantine(1-amino-3,5-dimethyladamantane) and neramexane(1-amino-1,3,3,5,5-pentamethylcyclohexane), are moderate affinity, uncompetitive NMDA receptor antagonists with strong voltage dependency and rapid blocking/unblocking kinetics. Therefore, there is an existing and continual need in the art for solid oral formulations of 1-aminocyclohexane compounds, and more preferably memantine HCl (1-amino-3,5-dimethyladamantane hydrochloride) and neramexane mesylate(1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate).
Solid oral drug compositions or preparations have various release profiles such as an immediate release profile as referenced by FDA guidelines (“Dissolution Testing of Immediate Release Solid Oral Dosage Forms”, issued August 1997, Section IV-A) or an extended release profile as referenced by FDA Guidelines (“Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations”, Food and Drug Administration, CDER, September 1997, Page 17). In the dissolution testing guideline for immediate release profiles, materials which dissolve at least 80% in the first 30 to 60 minutes in solution qualify as immediate release profiles. Therefore, immediate release solid dosage forms permit the release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible. In contrast, extended release solid oral dosage forms permit the release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over similarly extended time intervals, improve dosing compliance, and/or to modify other pharmacokinetic properties of the active ingredient.
U.S. Pat. No. 5,382,601 provides solid pharmaceutical dosage forms containing memantine, which exhibit an extended two-phase release profile, with a portion of the drug being released immediately, followed by a sustained release of the remainder. The matrix of this formulation contains both a water-soluble and a water-insoluble salt of casein, preferably sodium and calcium caseinate. However, casein has an unpleasant taste; it is associated with the undesirable effect of exacerbating some side effects as disclosed in U.S. Pat. No. 6,413,556; and displays instability in varying pH. Another concern regarding casein is the possibility of Bovine Spongiform Encephalitis (BSE) contamination or transmission of another infectious agent since casein is an animal-derived product.
A general method of preparing modified release N-methyl-D-aspartate (NMDA) receptor antagonists was described in U.S. Pat. No. 6,194,000. This method involves preparing an instant release component and a modified release component to arrive at the final formulation. The patent discloses the formulations consisting of encapsulated beads previously coated using organic solvent-based systems. However, this patent does not specifically disclose compositions containing memantine or neramexane. The patent also does not teach how the release rates affect the Tmax (time to maximum plasma concentration) or that this procedure will result in dose-proportional formulations.
Currently, a dosing regime of memantine of twice a day is employed using non-dose proportional immediate release tablets. After oral administration in man, memantine is completely absorbed (absolute bioavailability of approximately 100%). The time to maximum plasma concentrations (Tmax) following oral doses of 10 to 40 mg memantine ranged between 3 and 7 hours, with peak plasma concentrations (Cmax) after a single 20 mg oral dose ranging between 22 and 46 ng/mL. The AUC and Cmax values of memantine increase proportionally with dose over the dosage range of 5 to 40 mg. The elimination half-life (T1/2) of memantine is approximately 60-80 hours.
There is a need for dose-proportional memantine formulations which are readily achieved with immediate release formulations. Advantages of immediate release, dose-proportional formulations include improved ease of administration by allowing increases in dose without increasing the number of tablets that need to be administered, and increased flexibility in drug administration by allowing the target drug to be administered either as multiples of lower strength formulations or as one higher strength formulation. Another advantage of dose-proportional formulations of highly soluble and highly permeable drugs, particularly that of memantine and neramexane, is that the bioavailability of multiple strengths, e.g., 10 mg versus 80 mg, are considered identical and in accordance with the guidelines, “Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System”, U.S. Department of Health and Human Services, Food and Drug Administration. Administration of increasing drug doses are often required as part of an up-titration regimen to the desired therapeutic dose because such regimens result in improved tolerability. In fact, current guidelines for use of memantine in the treatment of Alzheimer's Disease recommend that memantine be administered as a starting dose of 5 mg/day and escalated to the 20 mg/day dose by weekly increases in the dose by 5 mg. Dose proportional formulations are especially important for the treatment of diseases, such as neuropathic pain, which require up-titration to higher doses. The existence of dose proportional, immediate release formulations of different strengths of memantine ranging from 2.5 mg to 80 mg would therefore, allow ease and convenience in dosing during both the up-titration phase and during maintenance at the higher therapeutic dose levels.